Indene derivatives and uses thereof
Inventors
Dolloff, Nathan G. • Robinson, Reeder M. • Reitz, Allen B. • Bian, Haiyan
Assignees
Leukogene Therapeutics Inc • MUSC Foundation for Research and Development • Fox Chase Chemical Diversity Center Inc
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Publication Number
US-10329269-B2
Publication Date
2019-06-25
Expiration Date
Abstract
The present invention relates to compounds of formula (I):including any stereochemically isomeric form thereof, or pharmaceutically acceptable salts thereof, for the treatment of, for example, cancer.
Core Innovation
The invention relates to indene-derivative compounds of formula (I), including stereoisomers and pharmaceutically acceptable salts, in the context of cancer treatment. The compounds are described for proteasome inhibitor-resistant multiple myeloma and other cancer cells showing proteasome inhibitor resistance.
The invention addresses proteasome inhibitor resistance in multiple myeloma and provides an approach for resensitization of proteasome inhibitor-resistant multiple myeloma. It also describes potentiation of proteasome inhibitor and histone deacetylase inhibitor therapies by inhibiting protein disulfide isomerase.
The disclosure further describes pharmaceutical compositions comprising the indene-derivative compounds or pharmaceutically acceptable salts thereof together with a pharmaceutically acceptable carrier, and cancer-treatment and anti-resistance methods associated with use of the compounds. Biological and biochemical data are presented to support increased sensitivity to proteasome inhibitor and to histone deacetylase inhibitors.
Claims Coverage
One independent claim is provided in the partial content and is directed to a compound, or pharmaceutically acceptable salt thereof. Dependent coverage adds a pharmaceutical composition comprising a therapeutically effective amount of the compound or salt and a pharmaceutically acceptable carrier.
Compound of formula (I) or pharmaceutically acceptable salt
A compound defined as an indene-derivative of formula (I), including stereoisomers, or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition with therapeutically effective amount and carrier
A pharmaceutical composition comprising a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
The claim coverage is directed to the defined compound structures or pharmaceutically acceptable salts and, in dependent form, to a pharmaceutical composition containing a therapeutically effective amount with a pharmaceutically acceptable carrier.
Stated Advantages
Proteasome inhibitor sensitization in PI-resistant MM.1S BzR cells versus bortezomib.
Potentiation of the second-generation proteasome inhibitor carfilzomib across multiple cancer cell types.
Broad spectrum single agent anti-tumor efficacy of E64FC26 across diverse tumor-derived cell lines.
Sensitization of cells to HDAC inhibitors, including panobinostat and other HDAC inhibitors.
In vivo anti-multiple myeloma activity in NSG mice, including alone and in combination with bortezomib.
Resensitization of proteasome inhibitor-resistant multiple myeloma.
Potentiation of proteasome inhibitor and histone deacetylase inhibitor therapies.
Inhibition of protein disulfide isomerase.
Documented Applications
Cancer treatment using indene-derivative compounds of formula (I).
Resensitization of proteasome inhibitor-resistant multiple myeloma.
Potentiation of proteasome inhibitor and histone deacetylase inhibitor therapies via inhibition of protein disulfide isomerase.
Use in combination therapy involving proteasome inhibitor therapy as described by the provided in vivo anti-MM activity results.
Cancer treatment, including multiple myeloma activity in vitro in MM.1S BzR cells and in vivo in NSG mice, and use of E64FC26 in combination with bortezomib.
Evaluation in multiple cancer cell types, including pancreatic cancer cells and T98G glioblastoma cells, as part of reported anti-tumor efficacy and sensitization to HDAC inhibitors.
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